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Research: Mechanisms of epigenetic signaling

Associate Professor of Chemical Biology and Medicinal Chemistry

UNC Eshelman School of Pharmacy
Joint Appointment in Biochemistry and Biophysics
(PhD – Rockefeller University and MD – Cornell)

ACCEPTING STUDENTS

Trained Faculty Mentor endorsed by Office of Graduate Ed UNC Chapel Hill

HONORS & AWARDS

  • 2017 Searle Scholar Award
  • 2017 Pew-Stewart Scholar for Cancer Research

RESEARCH

Despite every cell in the human body having a nearly identical genetic sequence, divergent patterns of gene expression lead to the development of diverse cell types and functions. These patterns are established through epigenetic changes to the composition and structure of chromatin, the physiologic state of the genome. The repeating unit of chromatin is the nucleosome, in which segments of genomic DNA are wrapped around molecular spools of histone proteins. By displaying diverse combinations of histone post-translational modifications, the nucleosome serves as an active signaling hub in the regulation of genome-templated processes. These processes, including gene expression, DNA replication and DNA damage repair, play fundamental roles in cell development and maintenance of genomic integrity. As such, inappropriate regulation of the epigenetic enzymes that write, read and erase these modifications is correlated with many human diseases, especially cancer.

Over the past two decades, structural and biochemical studies using peptide fragments of histone proteins have elucidated many mechanisms through which epigenetic enzymes recognize histone sequences and modification patterns. However, these peptide-based approaches preclude a fundamental understanding of how epigenetic signals are integrated within more physiologic states of chromatin.

McGinty Laboratory studies mechanisms governing epigenetic signaling at the nucleosome and chromatin levels. We use protein chemistry to reconstitute ‘designer’ nucleosomes and chromatin, containing defined patterns of post-translational modifications. When paired with structural biology, including X-ray crystallography and single particle cryo-EM, this allows us to interrogate mechanisms governing specific epigenetic signaling pathways at atomic resolution. Together with the Center for Integrative Chemical Biology and Drug Discovery, my lab will leverage our structural studies toward the design of small molecules to disrupt chromatin signaling pathways for basic research and therapeutic goals.

REPRESENTATIVE PUBLICATIONS

PubMed(click for Full Publication List) 

Budziszewski GR, Zhao Y, Spangler CJ, Kedziora KM, Williams MR, Azzam DN,
Skrajna A, Koyama Y, Cesmat AP, Simmons HC, Strauss JD, Kireev D, McGinty
RK#. Multivalent DNA and nucleosome acidic patch interactions specify VRK1
mitotic localization and activity. (in review at Nucleic Acids Res)

Spangler CJ, Yadav SP, Dongxu L, Geil CN, Smith CB, Wang GG*, Lee TH*, and
McGinty RK*. Dot1L activity in leukemia cells requires interaction with ubiquitylated
H2B that promotes productive nucleosome binding. Cell Reports. 2022 (accepted)

Spangler CJ and McGinty RK#. Determination of histone methyltransferase
structures in complex with the nucleosome by cryogenic electron microscopy.
Methods Mol Biol. 2022 (accepted)

Waybright JM, Clinkscales SE, Barnash KD, Budziszewski GR, Rectenwald JM,
Chiarella AM, NorrisDrouin JL, Cholensky SH, Pearce KH, Herring LE, McGinty
RK, Hathaway NA, and James LI. A peptidomimetic ligand targeting the
chromodomain of MPP8 reveals MPP8’s association with the HUSH complex. ACS
Chem Biol. 2021 Sep 17;16(9):17211736.

McGinty RK* and Tan S*. Principles of nucleosome recognition by chromatin
factors and enzymes. Curr Opin Struct Biol. 2021 Jun 28;71:1626.

Boyer JA, Spangler CJ, Strauss JD, Cesmat AP, Liu P, McGinty RK*, Zhang Q*.
Structural basis of nucleosomedependent cGAS inhibition. Science. 2020 Oct
23;370(6515):450454.

Skrajna A, Goldfarb D, Kedziora KM, Cousins EM, Grant GD, Spangler CJ, Barbour
EH, Yan X, Hathaway NA, Brown NG, Cook JG, Major MB, McGinty RK#.
Comprehensive nucleosome interactome screen establishes fundamental principles
of nucleosome binding. Nucleic Acids Res. 2020 Sep 25;48(17):94159432.

Anderson CJ, Baird MR, Hsu A, Barbour EH, Koyama Y, Borgnia MJ, McGinty
RK#. Structural Basis for Recognition of Ubiquitylated Nucleosome by Dot1L
Methyltransferase. Cell Reports. 2019 Feb 12;26(7):16811690.

Jeon J, McGinty RK, Muir TW, Kim JA, Kim J. Crosstalk among Set1 complex
subunits involved in H2B ubiquitylationdependent H3K4 methylation. Nucleic Acids
Res. 2018 Nov 30;46(21):1112911143.

Robert McGinty MD PhD